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Biomedical subjects

D L Jue

Publications and source records attributed to D L Jue.

At least 19 recordsLinked to original sources
PubMed1992

Hb Rancho Mirage [beta 143(H21)His----Asp]; a variant in the 2,3-DPG binding site showing normal oxygen affinity at physiological pH.

Hb Rancho Mirage was detected in a 17-year-old male in association with a mild anemia. Hemoglobin electrophoresis revealed the variant had a mobility between Hbs A and J on cellulose acetate (pH 8.6) and a mobility like Hb F on citrate agar (pH 6.4). A substitution of His----Asp was found at position 143 in the beta chain, a residue that contributes to the anionic 2,3-DPG binding site in Hb. This variant exhibited normal oxygen affinity at physiologic pH and reduced affinity at alkaline pH. This suggested a subtle shift in the allosteric equilibrium due most likely to the introduction of a negative charge that stabilized the 2,3-DPG pocket. Both homotrophic (heme-heme) and heterotropic (2,3-DPG and protons) effects were reduced; this might be a consequence of an alteration in the carboxyl terminal region of the beta-subunits. Although a His----Asp substitution would be considered to cause reasonable disruption of the 2,3-DPG and C-terminal conformation of the beta- subunits, the properties of Hb Rancho Mirage suggest that, in fact, there appear to be no major perturbation of the critical C-terminal residues.

2,3-Diphosphoglycerate↗
PubMed1990

Structural, functional, and subunit assembly properties of hemoglobin Attleboro [alpha 138 (H21) Ser----Pro], a variant possessing a site maturation at a critical C-terminal residue.

Hemoglobin Attleboro, a new alpha-chain variant with a substitution of proline for serine at position 138 (H21), was found to be a noncooperative high-affinity hemoglobin (P50 = 0.26 mmHg at pH 7 and 20 degrees C) which lacked an alkaline Bohr effect. Addition of 2,3-diphosphoglycerate (DPG) or inositol hexaphosphate (IHP) led to a decrease in oxygen affinity but to no alteration in either Bohr effect or cooperativity. Ligand binding kinetics studies revealed an overall rate of oxygen dissociation at pH 7.0 and 20 degrees C that was 2.7-fold slower than that for Hb A. At pH 8.5, the kinetic profile was identical with that at pH 7, confirming the absence of a Bohr effect for this variant hemoglobin. Measurement of the rate of oxygen dissociation with carbon monoxide replacement indicated a lack of cooperativity. Sedimentation velocity experiments yielded s20,w values of 2.8 and 4.3 for 65 microM solutions of oxyhemoglobins Attleboro and A, respectively (indicating an enhancement in the oxy dimer population of this variant). Studies of the carbon monoxide combination of this variant revealed an association rate 20-fold faster than that for Hb A; only in the presence of a 1000-fold molar excess of IHP was there a significant reduction in the overall rate. Rapid-scan and traditional stopped-flow experiments conducted in the Soret Soret region demonstrated an alteration in the structure and rate of assembly of the deoxy tetramer of Hb Attleboro relative to that of Hb A. The abnormal properties of this hemoglobin variant can be attributed to major perturbations in the C-terminal region.

Amino Acid Sequence↗
PubMed1989

Hb Catonsville (glutamic acid inserted between Pro-37(C2)alpha and Thr-38(C3)alpha). Nonallelic gene conversion in the globin system?

Hb Catonsville is an unstable variant in which glutamic acid is inserted into the alpha-globin chain between Pro-37(C2) and Thr-38(C3). The peptide sequence data are consistent with the DNA sequence of the polymerase chain reaction-amplified fragment of the variant globin gene, which shows the insertion of the triplet codon--GAA--into the mutant alpha-globin gene. In the normal alpha-globin gene cluster the codon for glutamic acid is GAG rather than GAA. Thus, there are two features unique to Hb Catonsville, one the insertion of a single residue into the interior of the alpha-globin chain, and two the presence of the alternate codon for glutamic acid. The experimental evidence suggests that Hb Catonsville may be an example of nonhomologous nonallelic gene conversion, an observation not previously reported in this gene family. The mutation occurs in the critical alpha 1 beta 2 interface of the hemoglobin tetramer and leads to a variant with high oxygen affinity, a reduced cooperativity, and Bohr effect.

Alleles↗
PubMed1989

Hb Hinsdale [beta 139 (H17)Asn----Lys]: a variant in the central cavity showing reduced affinity for oxygen and 2,3-diphosphoglycerate.

Hb Hinsdale was detected in two sisters and in a son and daughter of one of them as a band migrating in the Hb F position on cellulose acetate, pH 8.5. On citrate agar (pH 6.3) the variant hemoglobin has a mobility like that of Hb S. Hematologic data from these individuals appear normal except for mild anemia. Oxygen affinity studies show that the variant has low affinity for oxygen and reduced cooperativity. Results of tests for instability were negative. The mutation involves a site that lies in the central cavity close to the 2,3-diphosphoglycerate pocket, so it is not surprising that the variant shows a reduced ability to react with this effector molecule.

2,3-Diphosphoglycerate↗
PubMed1979

Hemoglobin Dunn: alpha 6 (A4) aspartic acid replaced by asparagine.

Hemoglobin Dunn, alpha 6 (A4) Asp leads to Asn was found in a 39-year-old black woman and her daughter. The hematological data on the propositus were normal and there were no apparent clinical or pathological findings associated with this abnormal hemoglobin. The structural characterization of this variant is described.

Adult↗
PubMed1977

Hemoglobin S Travis: a sickling hemoglobin with two amino acid substitutions [beta6(A3)glutamic acid leads to valine and beta142 (h20) alanine leads to valine).

Hb S Travis is a previously undescribed sickling hemoglobin with two amino acid substitutions in the beta chain: beta6 Glu leads to Val and beta142 Ala leads to Val. The beta6 Glu leads to Val mutation imparts to Hb S Travis the characteristic properties of sickling hemoglobin, namely its association with erythrocyte sickling, the insolubility of the hemoglobin in the reduced form, and a minimum gelling concentration value identical to Hb S. Unlike Hb S, Hb S Travis exhibits an increased oxygen affinity and a decreased affinity for 2,3-bisphosphoglycerate and inositol hexakisphosphate. In addition, the variant hemoglobin's tendency to autoxidize and its mechanical precipitability suggest that there are conformational differences between Hb S and Hb S Travis.

Alanine↗
PubMed1977

Hemoglobin Tarrant: alpha126(H9) Asp leads to Asn. A new hemoglobin variant in the alpha1beta1 contact region showing high oxygen affinity and reduced cooperativity.

Hemoglobin (Hb) Tarrant was detected by its electrophoretic mobility on cellulose acetate (pH 8.4) and citrate agar (pH 6.2). On cellulose acetate it moved as a band between hemoglobins F and S, and on citrate agar as a band at hemoglobin S. The test for solubility in 2 M phosphate buffer with Na2S2O4 was negative. The new variant has a substitution of asparagine for aspartic acid in position 126 of the alpha-chain, one of the sites involved in the alpha1beta1 contact. Furthermore, in deoxyhemoglobin aspartic acid 126 of each alpha chain also forms a non-covalent electrostatic salt bridge with arginine 141 of the corresponding alpha chain (Perutz, M. F. and Ten Eyck, L. F. (1972) Cold Spring Harbor Symp. Quant. Biol. 36, 295-310 and Perutz, M. F. (1970) Nature 228, 726-739). As a consequence of this substitution in hemoglobin Tarrant, the deoxy conformation or T state is destabilized because these two bridges cannot be formed. This condition is reflected in high oxygen affinity and low cooperativity.

Amino Acid Sequence↗
PubMed1976

Hemoglobin Fannin-Lubbock [alpha2 beta 2 119 (GH2) Gly replaced by Asp]. A new hemoglobin variant at the alpha1 beta 1 contact.

Hemoglobin Fannin-Lubbock was found in a 9-year-old Mexican-American female. The abnormal hemoglobin was detected as a fast-moving variant by electrophoresis on cellulose acetate at pH 8.4. Structural analysis indicated a substitution in the beta-chain of aspartic acid for glycine at position 119, a position involved in the alpha1beta1 contact of the hemoglobin tetramer. This contact between unlike chains is larger and undergoes a smaller shift during the process of oxygenation and deoxygenation that the alpha1beta2 contact (Perutz, M.F., Muirhead, H., Cox, J.M. and Goaman, L.C.G. (1968) Nature 219, 131-139). Mutations in this contact tend to cause slight or no changes in functional behavior. Apart from a mild anemia, the propositus did not exhibit any obvious clinical symptoms.

Amino Acids↗
PubMed1976

Hemoglobin Providence. A human hemoglobin variant occurring in two forms in vivo.

Hemoglobin Providence Asn and Hemoglobin Providence Asp are two abnormal hemoglobins which apparently arise from a single genetic change that substitutes asparagine for lysine at position 82 (EF6) in the beta chain of human hemoglobin. The second form appears to be thr result of a partial in vivo deamidation of the asparagine situated at position beta 82. Cellulose acetate and citrate agar electrophoresis of hemolysates from patients with this abnormality shows three bands. Globin chain electrophoresis at acid and alkaline pH shows three beta chains. These three chains correspond to the normal beta A chain and two abnormal beta chains. Sequence analysis indicates that the two abnormal chains differ from beta A at only position beta 82. In the two abnormal chains, the residue which is normally lysine is substituted either by asparagine or by aspartic acid. These substitutions are notable because beta 82 lysine is one of the residues involved in 2,3-diphosphoglycerate binding. Additionally, beta 82 lysine is typically invariant in hemoglobin beta chain sequences. Sequence data on the two forms of Hemoglobin Providence are given in this paper. The functional properties of these two forms are described in the next paper.

Adult↗